Optimizing Treatment of Follicular Lymphoma - Episode 10

Sequencing Strategies for Later-Line Therapy


John Gribben, MD, DSc: I think when we’re talking about follicular lymphoma, we’re hearing among us all a slight—not disagreement but lack of clarity on whether we need to be going for our most aggressive therapies first, or whether we have an approach of gentle therapy and keeping things for later on.

In CLL [chronic lymphocytic lymphoma], another indolent disease that we’re focusing on today, the data are much more clear: that using your most aggressive therapy up front results in the best outcome for the patients. We’re seeing overall survival advantages in that setting, and that disease was a much clearer algorithm in terms of using optimal therapies early on.

That data are still not here. We don’t have overall survival data that tell us exactly the sequence of events that we can have. What you’re left with is this hybrid of some patients starting very gently, other patients starting with chemoimmunotherapy plus maintenance. That approach alters the whole algorithm of where you are. Of course, we’ve also talked here as if we’re talking about going from 1 therapy to another to another, when in fact often you can go back to the previous lines of therapy. It’s not quite so clear-cut that you’re necessarily having to move from 1 class of agent to another. It depends exactly when the patient relapsed in the setting. I think we’re still struggling with what exactly the approach is that we’re taking for our patients.

Ian Flinn, MD: In terms of the John on the other side of the table, what’s your take on this notion? Do you hit people hard up front? I shouldn’t say hard—that sounds like it’s associated with adverse events—but like the CLL model. Or where are we doing a more gentle approach? Can you say anything about it? Is it individualized?

John Leonard, MD: Yeah. Generally speaking, I’m not taking that approach because unlike CLL, the advances in follicular lymphoma have been more incremental. I mean hitting it hard when you’re talking about chlorambucil versus ibrutinib in CLL. That’s a huge leap forward, as opposed to, for instance, obinutuzumab versus rituximab—or in my mind, rituximab maintenance, frankly.

Given the track record of lack of benefit, long term and survival, from early interventions and aggressive interventions in follicular lymphoma, until we have drugs that are a big leap forward, I think that there are definitely more big leaps forward; it’s harder for me to justify that. That said, there’s always wishful thinking, right? Sooner or later something is going to be that thing that we should be using sooner and should be treating more aggressively with earlier. But as of now, I don’t see it.

Ian Flinn, MD: This is an important question, so I want to get everyone’s take on this. Pier Luigi, what is your view of this?

Pier Luigi Zinzani, MD, PhD: I totally agree with John in term of a European view. It’s the situation where you can decide to start as soon as possible or you can wait, and the decision of what kind of treatment to do depends on the history of the patient. From the frontline and then the second line, and then also from the comorbidities of the patient, the age of the patients, the former start of the patient, these are several factors you can use to decide what to do in terms of third line, fourth line, and so on.

Ian Flinn, MD: Before we turn to new agents, Lori, do you agree with everybody, or do you have a different view?

Lori A. Leslie, MD: I am in agreement with everyone—I’ll try to be diplomatic. It’s really important to look at the CLL experience and comparatively highlight that we don’t know how to identify patients with risk models, whether it’s clinical, clinical molecular, or clinical genetic, to try to find who’s at risk for poor outcomes. Maybe by selecting patients at risk for poor outcome before treatment will help decide who you should hit hard from the beginning versus who can tolerate less intensive therapy and have a better course.

In CLL we’ve got FISH [fluorescence in situ hybridization], cytogenetics, IGVH mutation status, and p53 mutation, which help us predict the story for that patient. We’ve been trying, but in follicular we really don’t have anything similar to help select patients. I think if we did better selected studies, we probably would find a group of patients who would benefit from a more intensive versus less intensive up-front, or subsequent, approach. But we really have been unable to do so thus far.

John Gribben, MD, DSc: There is 1 thing to pick up on—that there’s the frequency of p53 abnormalities in follicular lymphoma. It’s exactly the same as the frequency in CLL frontline. And yet in CLL, it’s been a major factor on how you treat. Of course, that’s likely because we’ve got an agent that is able to be effective. But it’s long recognized in CLL worlds that giving chemoimmunotherapy makes no sense in those patients, yet we continue to give chemoimmunotherapy to the patients with follicular lymphoma who have that abnormality, that we aren’t even testing for it.

Ian Flinn, MD: I don’t even think we even know who has it, at least in the United States.

John Gribben, MD, DSc: Sure, but we know from the studies that have been done that the frequency is the same as it is in CLL. And we know when it has been looked at and that it has exactly the same true prognostic impact on immunotherapy. But what drives you not testing for it? What do we do if you’ve got it? We don’t have an answer. Maybe that would be the agent in whom you would consider using, as has been the model in CLL, very different therapy up front, avoiding chemotherapy completely, which makes sense in the absence of a functional p53.

Maybe it is time that we start to think about this and incorporate it. We’ve always got a lymph node biopsy. We’ve all got labs that test for p53 analysis. We could be doing it in follicular lymphoma, and it’s a little surprising to me that we aren’t doing it more.

Transcript Edited for Clarity